title: Embryonic stem cells, derived either after in vitro fertilization or nuclear transfer, prolong survival of semiallogeneic heart transplants.
abstract: Tolerance induction toward allogeneic organ grafts represents one of the major aims of transplantation medicine. Stem cells are promising candidates for promoting donor-specific tolerance. In this study, we investigated the immunomodulatory properties of murine embryonic stem cells (ESCs), obtained either by in vitro fertilization (IVF-ESCs) or by nuclear transfer (NT-ESCs), in heart transplant mouse models. IVF-ESCs did not prolong the survival of fully allogeneic cardiac transplants but significantly prolonged the survival of semiallogeneic hearts from the same ESC donor strain for >100 d in 44% of the animals. However, 28% of transplanted animals infused with IVF-ESCs experienced development of a teratoma. NT-ESCs similarly prolonged semiallogeneic heart graft survival (>100 d in 40% of the animals) but were less teratogenic. By in vitro studies, IVF-ESC and NT-ESC immunoregulation was mediated both by cell contact-dependent mechanisms and by the release of soluble factors. By adding specific inhibitors, we identified PGE(2) as a soluble mediator of ESC immunoregulation. Expansion of regulatory T cells was found in lymphoid organs and in the grafts of IVF-ESC- and NT-ESC-tolerized mice. Our study demonstrates that both IVF-ESCs and NT-ESCs modulate recipient immune response toward tolerance to solid organ transplantation, and that NT-ESCs exhibit a lower tendency for teratoma formation. Because NT-ESCs are obtained by NT of a somatic cell from living individuals into an enucleated oocyte, they could represent a source of donor-derived stem cells to induce tolerance to solid organ allograft.
authors.affiliation: Department of Molecular Medicine, Mario Negri Institute for Pharmacological Research, Bergamo 24125, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Imberti
authors.forename: Federica
authors.initials: F
authors.lastname: Casiraghi
authors.forename: Daniela
authors.initials: D
authors.lastname: Cugini
authors.forename: Nadia
authors.initials: N
authors.lastname: Azzollini
authors.forename: Paola
authors.initials: P
authors.lastname: Cassis
authors.forename: Marta
authors.initials: M
authors.lastname: Todeschini
authors.forename: Samantha
authors.initials: S
authors.lastname: Solini
authors.forename: Vittorio
authors.initials: V
authors.lastname: Sebastiano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zuccotti
authors.forename: Silvia
authors.initials: S
authors.lastname: Garagna
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Redi
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000276:immunology* / Q000637:transplantation*; D005260:Female; D005307:Fertilization in Vitro; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000379:methods / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000008:administration & dosage*; D011897:Random Allocation; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
chemical_list: D009687:Nuclear Proteins